Hypoxia induced exosomal circRNA promotes metastasis of Colorectal Cancer via targeting GEF-H1/RhoA axis

Abstract

Hypoxia is one of the important properties of solid tumor. However, oxygen supply within tumors is generally heterogeneous according to the distance from the nearest blood vessel. The discrepancy of metastatic potential exists between hypoxic cancer cells and relatively normoxic cancer cells. But the molecular mechanism remains poorly understood. Methods: Differential expression of circRNAs in plasma exosomes of CRC patients and normal subjects was performed by screening. Exosomes were isolated by ultra-centrifugation and RNA expressions were determined by RT-qPCR. The migratory capacity of cells was performed by high intension imaging, wound healing assay and transwell chamber migration assay. Results: Circ-133 is enriched in the plasma exosomes of CRC patients and increased with the disease progression. Exosomal circ-133 derived from hypoxic cells delivered into normoxic cells and promoted cancer metastasis by acting on miR-133a/GEF-H1/RhoA axis. Meanwhile, animal experiments revealed that knockdown of circ-133 can inhibit tumor metastasis. Circ-133 is expected to be a new biomarker for monitoring tumor progression and might be a novel therapeutic target. Conclusions: Hypoxia-derived exosomal circ-133 transported into normaxic cancer cells and promoted cell migration via miR-133a/GEF-H1/RhoA axis. This study reveals a potential mechanism for that the intra-tumor heterogeneity of oxygen promote cancer progression.

Carcinoma-associated fibroblasts derived exosomes modulate breast cancer cell stemness through exonic circHIF1A by miR-580-5p in hypoxic stress

“…Hypoxia is related to exosomes non-coding RNA. Previous studies reported that hypoxic BMSC-derived exosomal miRNAs promote metastasis of lung cancer cells 26 ; hypoxic cancer cell exosomal circ0048117 facilitates M2 macrophage polarization in esophageal squamous cell carcinoma 27 ; hypoxia-induced exosomal circRNA promotes metastasis of colorectal cancer via targeting GEF-H1/RhoA axis 28 ; hypoxia-associated circDENND2A promotes glioma aggressiveness by sponging miR-625-5p 29 . Our data demonstrated that circHIF1A from hypoxic CAFs exosomes promoted breast cancer stemness by regulating miR-580-5p targeting CD44 expression.…”

CircRNAs: a new target for the diagnosis and treatment of digestive system neoplasms

“…Yang et al found that Hypoxia-derived exosomal circ-133 transported into normaxic cancer cells and promoted cell migration via miR-133a/GEF-H1/RhoA axis. This reveals a potential mechanism for that the intra-tumor heterogeneity of oxygen promote cancer progression 89 . In addition, hsa_circ_0004585, hsa_circRNA_102958, circRNA_101951, circ_0060745, circ_0001946, circRNA_0000392, and circRNA_100876 are highly expressed in CRC and regulate tumor growth through their own pathways.…”

Exosomal circRNAs: Sorting Mechanisms, Roles and Clinical Applications in Tumors

“…Circ-133 is associated with hypoxia and regulates the distribution of E-cadherin protein on the cell membrane. Then, it was verified in vivo and vitro that exosomal circ-133 from hypoxic cells were transported to normal oxygenated cells through miR-133a/GEF-H1/RhoA axis, which regulated the distribution of E-cadherin membrane and promoted tumor metastasis (Yang et al, 2020).…”